Open Label Controlled Trial of Eculizumab in Adolescent Patients With Plasma Therapy-Resistant aHUS

• Sponsor: Alexion Pharmaceuticals (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00844844
• Collaborator: (none)
• Enrollment: 1
• Locations: 17
• Arm: 1
• Duration (Months): 50
• Patients Per Site: 0.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether eculizumab is safe and effective in the treatment of adolescent patients with plasma therapy-resistant Atypical Hemolytic-Uremic Syndrome (aHUS).

Condition or Disease	Intervention/Treatment	Phase
Atypical Hemolytic Uremic Syndrome	Drug: Eculizumab	Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 1 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-Label, Multi-Center Controlled Clinical Trial of Eculizumab in Adolescent Patients With Plasma Therapy-Resistant Atypical Hemolytic Uremic Syndrome (aHUS)
• Study Start Date: May 1, 2009
• Actual Primary Completion Date: Sep 1, 2010
• Actual Study Completion Date: Jul 1, 2013

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Eculizumab

Drug: Eculizumab; All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.

Outcome Measures

Primary Outcome Measures

1. Platelet Count Change From Baseline to 26 Weeks [From Baseline to 26 weeks]

2. Percentage of Patients With Platelet Count Normalization [Through 26 weeks]

   The primary objective of the study (per protocol) was to assess the effect of eculizumab to reduce TMA as measured by platelet count change from baseline (BL) during the Treatment Period (26 weeks) in patients with plasma therapy (PT)-resistant aHUS (protocol defined), including assessment of the proportion of patients who achieved Platelet Count Normalization from baseline through 26 weeks. Platelet Count Normalization was defined as the platelet count observed to be ≥150 x 10^9/L on at least two consecutive measurements which span a period of at least four weeks.

3. Percentage of Patients With Hematologic Normalization [Through 26 weeks]

   Hematologic Normalization was defined as normalization of both platelet count and lactic dehydrogenase (LDH) sustained for at least two consecutive measurements which spanned a period of at least four weeks.

Secondary Outcome Measures

1. Percentage of Patients With Complete TMA Response [Through 26 weeks]

   The proportion of patients who achieved a Complete TMA Response from baseline through 26 weeks of treatment with eculizumab was determined. Complete TMA Response was defined as Hematologic Normalization plus improvement in renal function (defined as ≥ 25% reduction from baseline in serum creatinine), which was sustained for two consecutive measurements over a period of at least four weeks.

2. TMA Intervention Rate [Through 26 weeks]

   TMA Intervention Rate (# PE/PI and # Dialysis Events/Patient/Day) in the eculizumab treatment period (from baseline through 26 weeks) for PE/PI and (from the fifteenth day following the first eculizumab dose through 26 weeks) for new dialysis events was compared with the TMA Intervention Rate during the pre-eculizumab treatment period.

3. Platelet Count Change From Baseline to 156 Weeks [From Baseline to 156 Weeks]

4. Percentage of Patients With Platelet Count Normalization [Through End of Study, Median Exposure 100.29 Weeks]

   Platelet Count Normalization was defined as the platelet count observed to be ≥150 x 10^9/L on at least two consecutive measurements which span a period of at least four weeks.

5. Percentage of Patients With Hematologic Normalization [Through End of Study, Median Exposure 100.29 Weeks]

   Hematologic Normalization was defined as normalization of both platelet count and lactic dehydrogenase (LDH) sustained for at least two consecutive measurements which spanned a period of at least four weeks.

6. Percentage of Patients With Complete TMA Response [Through End of Study, Median Exposure 100.29 Weeks]

   The proportion of patients who achieved a Complete TMA Response from baseline through end of the study was determined. Complete TMA Response was defined as Hematologic Normalization plus improvement in renal function (defined as ≥25% reduction from baseline in serum creatinine), which was sustained for two consecutive measurements over a period of at least four weeks.

7. TMA Intervention Rate [Through End of Study, Median Exposure 100.29 Weeks]

   TMA Intervention Rate (# PE/PI and # Dialysis Events/Patient/Day) in the eculizumab treatment period (from baseline through end of the study) for PE/PI and (from the fifteenth day following the first eculizumab dose through end of the study) for new dialysis events was compared with the TMA Intervention Rate during the pre-eculizumab treatment period.

8. Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration [Induction Phase for 4 weeks followed by Maintenance Phase starting on Week 5 through 26 weeks or longer]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 17 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Male or female patients from 12 and up to 18 years weighing ≥ 40 kg who have been diagnosed with Atypical Hemolytic-Uremic Syndrome (aHUS).

2. Decrease in platelet count despite at least 4 plasma therapy (PT) treatments in the 1 week immediately prior to screening.

3. Screening platelet count , < 150 x10^9/L and at least 25% lower than the average remission platelet count or

4. If remission counts not available, platelet count at onset of the current aHUS episode must be ≤75x10^{9/L and platelet count at screening must be ≤ 100 x 10}9/L despite PT treatment administration of at least 4 PT treatments in the 1 week immediately prior to screening

5. Known complement regulatory protein genetic abnormality

6. Lactate dehydrogenase (LDH) level ≥ ULN unless the patient has been receiving plasma exchange and LDH at the onset of the current aHUS episode was at least the ULN. If LDH is normal at screening, other markers indicative of ongoing hemolysis such as haptoglobin, schistocytes should be evaluated and discussed with Sponsor

7. Creatinine level ≥ ULN for age

8. Female patients of childbearing potential must be practicing an effective, reliable and medically approved contraceptive regimen during the entire duration of the study, including the follow-up period and for up to 5 months following of eculizumab treatment discontinuation.

9. Patient's parents/legal guardian must be willing and able to give written informed consent and patient must be willing to give written informed assent.

10. Able and willing to comply with study procedures.

Exclusion Criteria:

1. TTP, (defined as ADAMTS-13 activity <5%) from an historical observation (prior to initiation of plasma therapy) or as tested at the screening visit by the central laboratory

2. Malignancy within 5 years of screening.

3. Typical HUS (Shiga toxin +).

4. Known HIV infection.

5. Identified drug exposure-related HUS.

6. Infection-related HUS.

7. HUS related to bone marrow transplant

8. HUS related to vitamin B12 deficiency

9. Renal function status requiring chronic dialysis

10. Patients with a confirmed diagnosis of sepsis

11. Presence or suspicion of active and untreated systemic bacterial infection that, in the opinion of the Investigator confounds an accurate diagnosis of aHUS or impedes the ability to manage the aHUS disease.

12. Pregnancy or lactation.

13. Unresolved meningococcal disease.

14. Known Systemic Lupus Erythematosus (SLE) or antiphospholipid antibody positivity or syndrome.

15. Any medical or psychological condition that, in the opinion of the investigator, could increase the patient's risk by participating in the study or confound the outcome of the study.

16. Patients who have received previous treatment with eculizumab

17. Patients receiving IVIG within 8 weeks or Rituximab therapy within 12 weeks of screening.

18. Patients receiving other immunosuppressive therapies such as steroids, mTOR inhibitors or tacrolimus are excluded unless: [1] part of an established post-transplant anti-rejection regime, [2] patient has confirmed anti-CFH antibody requiring immunosuppressive therapy, and [3] dose of such medications have been unchanged for at least 4 weeks prior to the screening period or [4] patient is experiencing an acute aHUS relapse immediately after transplant

19. Patients receiving Erythrocyte Stimulating Agents (ESAs) unless already on a stable dose for at least 4 weeks prior to the screening period or a washout period of at least 2 weeks from the last dose of ESA therapy.

20. Participation in any other investigational drug trial or exposure to other investigational agent, device, or procedures beginning 4 weeks prior to screening and throughout the entire trial.

21. Hypersensitivity to eculizumab, to murine proteins or to one of the excipients

22. Patients between ages from 12 and up to 18 years weighing < 40 kg

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1		Atlanta	Georgia	United States	30322
2		Fort Wayne	Indiana	United States	46804
3		New York	New York	United States	10032
4		New York	New York	United States	10065
5		Grapevine	Texas	United States	76051
6		Houston	Texas	United States	77030
7		Innsbruck		Austria	6020
8		Bordeaux		France	33076
9		Lyon		France	69437
10		Nantes		France	44093
11		Paris		France	75743
12		Quimper		France	29107
13		Saint Priest en Jarez		France	42270
14		Tours		France	37044
15		Aachen		Germany	52074
16		Essen		Germany	45147
17		Newcastle		United Kingdom	NE7 7DN

Sponsors and Collaborators

• Alexion Pharmaceuticals

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Alexion Pharmaceuticals
• ClinicalTrials.gov Identifier: NCT00844844
• Other Study ID Numbers: C08-002B; BB-IND-11075; EudraCT Number 2008-006953-41
• First Posted: Feb 16, 2009
• Last Update Posted: Jul 23, 2015
• Last Verified: Jun 1, 2015

• Keywords provided by Alexion Pharmaceuticals: aHUS
• Additional relevant MeSH terms: Hemolytic-Uremic Syndrome; Atypical Hemolytic Uremic Syndrome; Syndrome; Hemolysis; Eculizumab

Study Results

Participant Flow

Recruitment Details	C08-002A/B combined 2 studies: one for adults (C08-002A, N=16) and one for adolescents (C08-002B, N=1) Please refer to NCT00844545 for combined studies with enrollment number corresponding to each individual study
Pre-assignment Detail	Patients had to exhibit a decrease in platelet count despite at least 4 Plasma Therapy (PT) treatments in the 1 week immediately prior to screening. Patients who met the eligibility criteria during screening were enrolled into the Treatment Period which commenced with the first eculizumab dose.

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Period Title: Screening Period
STARTED	17
COMPLETED	17
NOT COMPLETED	0
Period Title: Screening Period
STARTED	17
COMPLETED	15
NOT COMPLETED	2
Period Title: Screening Period
STARTED	13
COMPLETED	11
NOT COMPLETED	2
Period Title: Screening Period
STARTED	6
COMPLETED	5
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Overall Participants	17
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	31.8 (13.32)
Sex: Female, Male (Count of Participants)
Female	12 70.6%
Male	5 29.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	1 5.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 5.9%
White	15 88.2%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Platelet Count Change From Baseline to 26 Weeks
Time Frame	From Baseline to 26 weeks

Outcome Measure Data

Analysis Population Description

Change from baseline platelet counts were analyzed for the ITT population using a repeated measurement ANOVA model. A least squares (LS) mean for the change from baseline was produced for each study visit for which a measurement of platelet count was scheduled. Significance of change was assessed at the 5% level at each time point.

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Measure Participants	17
Least Squares Mean (95% Confidence Interval) [10^9 cells/L]	65.18

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	With at least 12 patients enrolled and assuming a null hypothesis of no post-dose change from baseline in mean platelet count, the study had approximately 88% power to detect as statistically significant an effect size (mean change from baseline/standard deviation) of at least 1 when using a one sample t-test with a two-sided α=0.05. All analyses were based on the pooled data from the two protocols:C08-002A (adult) and C08-002B (Adolescent), a similar protocol, for patients <18 years with aHUS.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	Change from baseline were analyzed using a repeated measurement ANOVA model with time and baseline as fixed effects and subject as a random effect.
Method of Estimation	Estimation Parameter	LS mean change from baseline
	Estimated Value	65.18
	Confidence Interval	(2-Sided) 95%; 37.01 to 93.36
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Percentage of Patients With Platelet Count Normalization
Description	The primary objective of the study (per protocol) was to assess the effect of eculizumab to reduce TMA as measured by platelet count change from baseline (BL) during the Treatment Period (26 weeks) in patients with plasma therapy (PT)-resistant aHUS (protocol defined), including assessment of the proportion of patients who achieved Platelet Count Normalization from baseline through 26 weeks. Platelet Count Normalization was defined as the platelet count observed to be ≥150 x 10^9/L on at least two consecutive measurements which span a period of at least four weeks.
Time Frame	Through 26 weeks

Outcome Measure Data

Analysis Population Description

The Tabulations of the proportion of patients who achieved platelet count normalization through 26 weeks were performed for the ITT population. Exact binomial confidence intervals were produced for the analysis.

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Measure Participants	17
Number (95% Confidence Interval) [Percentage of Participants]	82 482.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients < 18 years of age for adolescent patients with aHUS.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent of platelet count normalization
	Estimated Value	82
	Confidence Interval	(2-Sided) 95%; 57 to 96
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Percentage of Patients With Hematologic Normalization
Description	Hematologic Normalization was defined as normalization of both platelet count and lactic dehydrogenase (LDH) sustained for at least two consecutive measurements which spanned a period of at least four weeks.
Time Frame	Through 26 weeks

Outcome Measure Data

Analysis Population Description

Tabulations of the proportion of patients who achieved a hematologic normalization through 26 weeks were performed for the ITT population. Exact binomial confidence intervals were produced for the analysis.

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Measure Participants	17
Number (95% Confidence Interval) [Percentage of Participants]	76 447.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients < 18 years of age for adolescent patients with aHUS.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent of hematologic normalization
	Estimated Value	76
	Confidence Interval	(2-Sided) 95%; 50 to 93
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage of Patients With Complete TMA Response
Description	The proportion of patients who achieved a Complete TMA Response from baseline through 26 weeks of treatment with eculizumab was determined. Complete TMA Response was defined as Hematologic Normalization plus improvement in renal function (defined as ≥ 25% reduction from baseline in serum creatinine), which was sustained for two consecutive measurements over a period of at least four weeks.
Time Frame	Through 26 weeks

Outcome Measure Data

Analysis Population Description

Tabulations of the proportion of patients who achieved a complete TMA response from baseline through 26 weeks were performed. For this endpoint, for any relevant proportions, exact binomial confidence intervals were produced.

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Measure Participants	17
Number (95% Confidence Interval) [Percentage of Participants]	65 382.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients < 18 years of age for adolescent patients with aHUS.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent of complete TMA response
	Estimated Value	65
	Confidence Interval	(2-Sided) 95%; 38 to 86
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	TMA Intervention Rate
Description	TMA Intervention Rate (# PE/PI and # Dialysis Events/Patient/Day) in the eculizumab treatment period (from baseline through 26 weeks) for PE/PI and (from the fifteenth day following the first eculizumab dose through 26 weeks) for new dialysis events was compared with the TMA Intervention Rate during the pre-eculizumab treatment period.
Time Frame	Through 26 weeks

Outcome Measure Data

Analysis Population Description

A signed rank test assessed differences in magnitudes of change in TMA intervention rate between the pre-eculizumab treatment period and during eculizumab treatment period for ITT population.

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Measure Participants	17
Mean (Standard Deviation) [# events/patient/day]	0.04 (0.10)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients < 18 years of age for adolescent patients with aHUS.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.78
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Platelet Count Change From Baseline to 156 Weeks
Time Frame	From Baseline to 156 Weeks

Outcome Measure Data

Analysis Population Description

Change from baseline platelet counts were analyzed for the ITT population using a repeated measurement ANOVA model. A least squares (LS) mean for the change from baseline was produced for each study day for which a measurement of platelet count was scheduled. Significance of change was assessed at the 5% level at each time point.

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Measure Participants	17
Least Squares Mean (95% Confidence Interval) [10^9 cells/L]	111.62

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients < 18 years of age for adolescent patients with aHUS.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANOVA
	Comments	Change from baseline was analyzed using a repeated measurement ANOVA model with time and baseline as fixed effects and subject as a random effect.
Method of Estimation	Estimation Parameter	LS mean change from baseline
	Estimated Value	111.62
	Confidence Interval	(2-Sided) 95%; 98.12 to 125.13
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage of Patients With Platelet Count Normalization
Description	Platelet Count Normalization was defined as the platelet count observed to be ≥150 x 10^9/L on at least two consecutive measurements which span a period of at least four weeks.
Time Frame	Through End of Study, Median Exposure 100.29 Weeks

Outcome Measure Data

Analysis Population Description

The Tabulations of the proportion of patients who achieved platelet count normalization through end of the study were performed for the ITT population. Exact binomial confidence intervals were produced for the analysis.

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Measure Participants	17
Number (95% Confidence Interval) [Percentage of Participants]	88 517.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients < 18 years of age for adolescent patients with aHUS.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent of platelet count normalization
	Estimated Value	88
	Confidence Interval	(2-Sided) 95%; 64 to 99
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percentage of Patients With Hematologic Normalization
Description	Hematologic Normalization was defined as normalization of both platelet count and lactic dehydrogenase (LDH) sustained for at least two consecutive measurements which spanned a period of at least four weeks.
Time Frame	Through End of Study, Median Exposure 100.29 Weeks

Outcome Measure Data

Analysis Population Description

Tabulations of the proportion of patients who achieved a hematologic normalization through end of study were performed for the ITT population. Exact binomial confidence intervals were produced for the analysis.

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Measure Participants	17
Number (95% Confidence Interval) [Percentage of Participants]	88 517.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients < 18 years of age for adolescent patients with aHUS.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent of hematologic normalization
	Estimated Value	88
	Confidence Interval	(2-Sided) 95%; 64 to 99
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Secondary Outcome

Title	Percentage of Patients With Complete TMA Response
Description	The proportion of patients who achieved a Complete TMA Response from baseline through end of the study was determined. Complete TMA Response was defined as Hematologic Normalization plus improvement in renal function (defined as ≥25% reduction from baseline in serum creatinine), which was sustained for two consecutive measurements over a period of at least four weeks.
Time Frame	Through End of Study, Median Exposure 100.29 Weeks

Outcome Measure Data

Analysis Population Description

Tabulations of the proportion of patients who achieved a complete TMA response from baseline through end of study were performed. For this endpoint, for any relevant proportions, exact binomial confidence intervals were produced.

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Measure Participants	17
Number (95% Confidence Interval) [Percentage of Participants]	76 447.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients < 18 years of age for adolescent patients with aHUS.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Percent of complete TMA response
	Estimated Value	76
	Confidence Interval	(2-Sided) 95%; 50 to 93
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Secondary Outcome

Title	TMA Intervention Rate
Description	TMA Intervention Rate (# PE/PI and # Dialysis Events/Patient/Day) in the eculizumab treatment period (from baseline through end of the study) for PE/PI and (from the fifteenth day following the first eculizumab dose through end of the study) for new dialysis events was compared with the TMA Intervention Rate during the pre-eculizumab treatment period.
Time Frame	Through End of Study, Median Exposure 100.29 Weeks

Outcome Measure Data

Analysis Population Description

A signed rank test assessed differences in magnitudes of change in TMA intervention rate between the pre-eculizumab treatment period and during eculizumab treatment period for ITT population.

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Measure Participants	17
Mean (Standard Deviation) [# events/patient/day]	0.04 (0.11)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Eculizumab
	Comments	All analyses were based on the pooled data from the two protocols: protocol C08-002A for adult patients with aHUS and protocol C08-002B, a similar protocol, for patients < 18 years of age for adolescent patients with aHUS.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	Wilcoxon (Mann-Whitney)
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.78
	Confidence Interval	(2-Sided) %; to
	Parameter Dispersion	Type: Value:
	Estimation Comments

11. Secondary Outcome

Title	Pharmacokinetics (PK) and Pharmacodynamics (PD); Minimum and Maximum Blood Concentration
Time Frame	Induction Phase for 4 weeks followed by Maintenance Phase starting on Week 5 through 26 weeks or longer

Outcome Measure Data

Analysis Population Description

PK parameters Cmin and Cmax were estimated using a population PK model developed from the observed PK concentration data

Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
Measure Participants	17
max concentration during induction period	145.16 (26.56)
min concentration during induction period	93.66 (22.10)
max concentration during maintenace	345.14 (89.74)
Min concentration during maintenance	151.80 (68.16)

Adverse Events

Time Frame	Through end of study; Exposure to eculizumab in this study extended for a median of 100 weeks and ranged from two weeks to 186 weeks.
Adverse Event Reporting Description	At every visit, patients were asked a standard non-leading question to elicit any changes in their medical well-being including inquiry about any hospitalization, accidents, and new or changed concomitant medication regimens. AEs were also documented from any data collected (e.g. laboratory values, physical examination findings, ECG changes, etc.).
Arm/Group Title	Eculizumab
Arm/Group Description	All patients received open-label eculizumab administered intravenously on the following dose schedule: Induction dose - 900 mg per week for four weeks and a dose of 1200 mg one week later; Maintenance dose - 1200 mg every two weeks. Patients who received plasma exchange or infusion during the eculizumab treatment period received a supplemental dose of 600 mg within one hour before plasma infusion or within one hour after the completion of each plasma exchange.
All Cause Mortality
	Eculizumab
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Eculizumab
	Affected / at Risk (%)	# Events
Total	17/17 (100%)
Blood and lymphatic system disorders
Anaemia	1/17 (5.9%)
Haemolytic anaemia	1/17 (5.9%)
Haemolytic uraemic syndrome	1/17 (5.9%)
Leukopenia	1/17 (5.9%)
Pancytopenia	1/17 (5.9%)
Cardiac disorders
Bradycardia	1/17 (5.9%)
Pericardial effusion	1/17 (5.9%)
Gastrointestinal disorders
Abdominal pain	1/17 (5.9%)
Gastritis	1/17 (5.9%)
Ileus	1/17 (5.9%)
Oesophagitis	1/17 (5.9%)
Pancreatitis acute	1/17 (5.9%)
Vomiting	1/17 (5.9%)
General disorders
Pyrexia	1/17 (5.9%)
Hepatobiliary disorders
Cholelithiasis	1/17 (5.9%)
Immune system disorders
Transplant rejection	1/17 (5.9%)
Infections and infestations
Asymptomatic bacteriuria	1/17 (5.9%)
Bronchitis	1/17 (5.9%)
Escherichia sepsis	1/17 (5.9%)
Gastroenteritis	1/17 (5.9%)
Upper respiratory tract infection	2/17 (11.8%)
Urinary tract infection	1/17 (5.9%)
Varicella	1/17 (5.9%)
Injury, poisoning and procedural complications
Respiratory fume inhalation disorder	1/17 (5.9%)
Musculoskeletal and connective tissue disorders
Back pain	1/17 (5.9%)
Systemic lupus erythematosus	1/17 (5.9%)
Nervous system disorders
Convulsion	1/17 (5.9%)
Headache	1/17 (5.9%)
Posterior reversible encephalopathy syndrome	1/17 (5.9%)
Psychiatric disorders
Alcohol withdrawal syndrome	1/17 (5.9%)
Renal and urinary disorders
Haematuria	1/17 (5.9%)
Renal failure acute	1/17 (5.9%)
Renal impairment	3/17 (17.6%)
Reproductive system and breast disorders
Adenomyosis	1/17 (5.9%)
Metrorrhagia	1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/17 (5.9%)
Vascular disorders
Accelerated hypertension	2/17 (11.8%)
Embolism venous	1/17 (5.9%)
Hypertension	3/17 (17.6%)
Malignant hypertension	2/17 (11.8%)
Other (Not Including Serious) Adverse Events
	Eculizumab
	Affected / at Risk (%)	# Events
Total	17/17 (100%)
Blood and lymphatic system disorders
Anaemia	6/17 (35.3%)
Iron deficiency anaemia	1/17 (5.9%)
Leukopenia	3/17 (17.6%)
Lymphopenia	1/17 (5.9%)
Neutropenia	1/17 (5.9%)
Thrombocytopenia	1/17 (5.9%)
Cardiac disorders
Bradycardia	2/17 (11.8%)
Pericardial effusion	1/17 (5.9%)
Ear and labyrinth disorders
Cerumen impaction	1/17 (5.9%)
Vertigo	1/17 (5.9%)
Endocrine disorders
Cushingoid	1/17 (5.9%)
Hyperparathyroidism secondary	1/17 (5.9%)
Hypothalamo-pituitary disorder	1/17 (5.9%)
Eye disorders
Cataract	1/17 (5.9%)
Conjunctival haemorrhage	1/17 (5.9%)
Conjunctival hyperaemia	1/17 (5.9%)
Conjunctivitis	1/17 (5.9%)
Eye pain	1/17 (5.9%)
Photophobia	1/17 (5.9%)
Gastrointestinal disorders
Abdominal pain	1/17 (5.9%)
Abdominal pain upper	1/17 (5.9%)
Dental caries	2/17 (11.8%)
Diarrhoea	8/17 (47.1%)
Food poisoning	1/17 (5.9%)
Gastritis	1/17 (5.9%)
Gastrointestinal pain	1/17 (5.9%)
Glossodynia	1/17 (5.9%)
Haemorrhoids	1/17 (5.9%)
Impaired gastric emptying	1/17 (5.9%)
Nausea	5/17 (29.4%)
Oral pain	1/17 (5.9%)
Rectal haemorrhage	1/17 (5.9%)
Toothache	3/17 (17.6%)
Vomiting	8/17 (47.1%)
General disorders
Asthenia	3/17 (17.6%)
Chest discomfort	1/17 (5.9%)
Chest pain	2/17 (11.8%)
Cyst	1/17 (5.9%)
Face oedema	1/17 (5.9%)
Fatigue	3/17 (17.6%)
Influenza like illness	1/17 (5.9%)
Oedema	1/17 (5.9%)
Oedema peripheral	5/17 (29.4%)
Pain	3/17 (17.6%)
Pyrexia	3/17 (17.6%)
Tenderness	1/17 (5.9%)
Thirst	1/17 (5.9%)
Hepatobiliary disorders
Cholestasis	1/17 (5.9%)
Hepatocellular injury	1/17 (5.9%)
Immune system disorders
Hypersensitivity	1/17 (5.9%)
Seasonal allergy	2/17 (11.8%)
Infections and infestations
Abscess	1/17 (5.9%)
Bronchitis	4/17 (23.5%)
Campylobacter infection	1/17 (5.9%)
Conjunctivitis infective	1/17 (5.9%)
Cystitis	1/17 (5.9%)
Ear infection	1/17 (5.9%)
Fungal infection	1/17 (5.9%)
Gastroenteritis	3/17 (17.6%)
Genital herpes	1/17 (5.9%)
Haemophilus infection	1/17 (5.9%)
Herpes zoster	2/17 (11.8%)
Impetigo	1/17 (5.9%)
Influenza	2/17 (11.8%)
Lower respiratory tract infection	1/17 (5.9%)
Nasopharyngitis	3/17 (17.6%)
Onychomycosis	1/17 (5.9%)
Papilloma viral infection	1/17 (5.9%)
Pharyngitis	1/17 (5.9%)
Pharyngitis streptococcal	1/17 (5.9%)
Rhinitis	3/17 (17.6%)
Sinusitis	2/17 (11.8%)
Staphylococcal infection	1/17 (5.9%)
Tonsillitis	1/17 (5.9%)
Tooth abscess	2/17 (11.8%)
Tooth infection	1/17 (5.9%)
Tracheobronchitis	1/17 (5.9%)
Upper respiratory tract infection	4/17 (23.5%)
Urinary tract infection	6/17 (35.3%)
Urinary tract infection bacterial	1/17 (5.9%)
Injury, poisoning and procedural complications
Arteriovenous fistula aneurysm	1/17 (5.9%)
Contusion	1/17 (5.9%)
Excoriation	1/17 (5.9%)
Eye injury	1/17 (5.9%)
Incision site oedema	1/17 (5.9%)
Laceration	2/17 (11.8%)
Muscle rupture	1/17 (5.9%)
Vascular graft complication	1/17 (5.9%)
Investigations
Antibiotic resistant Staphylococcus test positive	1/17 (5.9%)
Blood lactate dehydrogenase increased	2/17 (11.8%)
Carbon dioxide abnormal	1/17 (5.9%)
Haematocrit decreased	1/17 (5.9%)
Haemoglobin decreased	1/17 (5.9%)
Haptoglobin decreased	1/17 (5.9%)
Reticulocyte count increased	1/17 (5.9%)
Vitamin D decreased	1/17 (5.9%)
Weight decreased	1/17 (5.9%)
Metabolism and nutrition disorders
Acidosis	2/17 (11.8%)
Dehydration	1/17 (5.9%)
Dyslipidaemia	2/17 (11.8%)
Fluid overload	1/17 (5.9%)
Fluid retention	1/17 (5.9%)
Hyperkalaemia	1/17 (5.9%)
Hyperlipidaemia	1/17 (5.9%)
Hyperphosphataemia	2/17 (11.8%)
Hypocalcaemia	1/17 (5.9%)
Hypokalaemia	3/17 (17.6%)
Hypomagnesaemia	2/17 (11.8%)
Iron deficiency	1/17 (5.9%)
Metabolic acidosis	1/17 (5.9%)
Obesity	1/17 (5.9%)
Vitamin D deficiency	1/17 (5.9%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/17 (5.9%)
Back pain	3/17 (17.6%)
Bone pain	1/17 (5.9%)
Flank pain	1/17 (5.9%)
Intervertebral disc degeneration	1/17 (5.9%)
Joint swelling	2/17 (11.8%)
Muscle spasms	2/17 (11.8%)
Myalgia	1/17 (5.9%)
Neck pain	1/17 (5.9%)
Osteopenia	1/17 (5.9%)
Pain in extremity	1/17 (5.9%)
Systemic lupus erythematosus	1/17 (5.9%)
Tendonitis	1/17 (5.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Uterine leiomyoma	1/17 (5.9%)
Nervous system disorders
Ageusia	1/17 (5.9%)
Dizziness	3/17 (17.6%)
Headache	7/17 (41.2%)
Lethargy	2/17 (11.8%)
Loss of consciousness	1/17 (5.9%)
Migraine	2/17 (11.8%)
Paraesthesia	1/17 (5.9%)
Peripheral sensory neuropathy	1/17 (5.9%)
Presyncope	1/17 (5.9%)
Sinus headache	1/17 (5.9%)
Syncope	1/17 (5.9%)
Tremor	1/17 (5.9%)
Psychiatric disorders
Alcoholism	1/17 (5.9%)
Anxiety	1/17 (5.9%)
Depression	1/17 (5.9%)
Dysthymic disorder	1/17 (5.9%)
Insomnia	4/17 (23.5%)
Nervousness	1/17 (5.9%)
Sleep disorder	1/17 (5.9%)
Renal and urinary disorders
Dysuria	2/17 (11.8%)
Haematuria	1/17 (5.9%)
Nephropathy toxic	1/17 (5.9%)
Pollakiuria	1/17 (5.9%)
Proteinuria	2/17 (11.8%)
Renal failure acute	1/17 (5.9%)
Renal impairment	2/17 (11.8%)
Renal pain	1/17 (5.9%)
Reproductive system and breast disorders
Adenomyosis	1/17 (5.9%)
Breast calcifications	1/17 (5.9%)
Cervical dysplasia	1/17 (5.9%)
Menorrhagia	2/17 (11.8%)
Metrorrhagia	1/17 (5.9%)
Ovarian cyst	2/17 (11.8%)
Uterine malposition	1/17 (5.9%)
Vulvovaginal discomfort	1/17 (5.9%)
Respiratory, thoracic and mediastinal disorders
Cough	4/17 (23.5%)
Dyspnoea	2/17 (11.8%)
Dyspnoea exertional	1/17 (5.9%)
Emphysema	1/17 (5.9%)
Epistaxis	2/17 (11.8%)
Nasal congestion	1/17 (5.9%)
Nasal septum deviation	1/17 (5.9%)
Oropharyngeal pain	2/17 (11.8%)
Pleural effusion	1/17 (5.9%)
Productive cough	1/17 (5.9%)
Rhinorrhoea	1/17 (5.9%)
Sinus congestion	1/17 (5.9%)
Upper-airway cough syndrome	1/17 (5.9%)
Skin and subcutaneous tissue disorders
Dermatitis	1/17 (5.9%)
Dermatitis contact	2/17 (11.8%)
Dry skin	2/17 (11.8%)
Erythema	2/17 (11.8%)
Increased tendency to bruise	1/17 (5.9%)
Pruritus	2/17 (11.8%)
Rash	2/17 (11.8%)
Skin depigmentation	1/17 (5.9%)
Skin disorder	1/17 (5.9%)
Skin irritation	1/17 (5.9%)
Skin lesion	1/17 (5.9%)
Urticaria	1/17 (5.9%)
Surgical and medical procedures
Tooth extraction	1/17 (5.9%)
Vascular disorders
Haematoma	2/17 (11.8%)
Hypertension	7/17 (41.2%)
Hypotension	2/17 (11.8%)
Orthostatic hypotension	1/17 (5.9%)
Poor venous access	1/17 (5.9%)
Thrombophlebitis superficial	1/17 (5.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Participation in this multicenter study involved a commitment to publish the data from the study in a cooperative publication prior to release of study results on an individual basis.